{
  "abstract": "The GDF15-GFRAL-RET neuroendocrine axis is a key regulator of body-weight homeostasis and metabolic control. GFRAL, a hindbrain-restricted receptor for the stress-responsive cytokine GDF15, signals by assembling a ternary complex with GDF15 and the tyrosine kinase RET. Pathological hyperactivation of this axis drives disease-associated weight loss, including cancer-associated cachexia. Here, we report a GFRAL-binding and GDF15-GFRAL pathway-blocking antibody (GB2Ab) and its humanized lead with potent preclinical efficacy. The GB2Ab Fab-GFRAL D3 crystal structure reveals an induced-fit mechanism in which GB2Ab sterically occludes the GFRAL-RET interface and remodels the primary RET CLD1-CLD2 binding site, providing a structural basis for high-affinity binding, slow dissociation, and potent antagonism. Structure-guided humanization preserves high-affinity and cross-reactivity. The humanized antibody reaches the area postrema, attenuates GDF15-evoked neural activation, ameliorates cachectic phenotypes, and suppresses sympathetic preganglionic activity in an orthotopic cancer cachexia model, establishing receptor-centric GDF15-GFRAL-RET antagonism as a promising strategy for cancer-associated cachexia and other GDF15-driven diseases.",
  "abstract_shown": true,
  "affiliations": [
    "Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.",
    "Life Science Research Institute, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.",
    "THOR Therapeutics Inc; Daejeon 34134, Republic of Korea.",
    "Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.",
    "InnoCORE AI-CRED Institute, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.",
    "Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham; Birmingham, AL, USA."
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Sohyun Kim",
      "orcid": "0000-0001-5701-7602"
    },
    {
      "affs": [
        2
      ],
      "name": "Min Hee Lee",
      "orcid": "0000-0002-7403-7274"
    },
    {
      "affs": [
        3
      ],
      "name": "Jinsook Ahn",
      "orcid": "0000-0002-4175-5181"
    },
    {
      "affs": [
        4
      ],
      "name": "Sang-Hyeon Ju",
      "orcid": "0000-0001-7098-4648"
    },
    {
      "affs": [
        3
      ],
      "name": "Dong Sun Lee",
      "orcid": "0000-0002-9385-6136"
    },
    {
      "affs": [
        0
      ],
      "name": "Seohyun Choi",
      "orcid": "0009-0000-2191-5419"
    },
    {
      "affs": [
        5
      ],
      "name": "Kwang Wook Min",
      "orcid": "0000-0002-7593-7047"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Minho Shong",
      "orcid": "0000-0002-0247-7115"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Ho Min Kim",
      "orcid": "0000-0003-0029-3643"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2r7mj8870a7gs.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aee5992",
  "fulltext_url": "https://europepmc.org/articles/PMC13715715",
  "id": "2r7mj8870a7gs",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/abs/10.1126/sciadv.aee5992",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Biomedicine and Life Sciences"
    ],
    [
      "heading",
      "Diseases and Disorders"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "heading",
      "SciAdv r-articles"
    ],
    [
      "heading",
      "Structural Biology"
    ],
    [
      "openalex",
      "2745|GDF15 and Related Biomarkers"
    ]
  ],
  "openalex": "W7224082834",
  "pdf_url": "https://europepmc.org/articles/PMC13715715?pdf=render",
  "pmcid": "PMC13715715",
  "pmid": "42950051",
  "published": "2026-10-28",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/2r7mj8870a7gs.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:16Z",
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      "source": "feed-science",
      "url": "https://www.science.org/doi/abs/10.1126/sciadv.aee5992"
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    {
      "first_seen": "2026-10-30T12:17:41Z",
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      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aee5992"
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      "first_seen": "2026-10-31T00:20:33Z",
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      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42950051"
    },
    {
      "first_seen": "2026-11-01T12:22:56Z",
      "native_id": "PMC13715715",
      "source": "pmc",
      "url": "https://doi.org/10.1126/sciadv.aee5992"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "heading:Structural Biology",
      "subfield": "structural-biology"
    }
  ],
  "title": "Induced-fit anti-GFRAL antibody ameliorates cancer cachexia and attenuates sympathetic outflow in tumor-bearing mice",
  "title_text": "Induced-fit anti-GFRAL antibody ameliorates cancer cachexia and attenuates sympathetic outflow in tumor-bearing mice",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:22:56Z",
  "url": "https://research.draconitic.com/paper/2r7mj8870a7gs",
  "venue": "Science Advances",
  "versions": []
}